Kala-azar is a protracted disease caused by the protozoan (zoonotic) or (anthroponotic), transmitted by sandflies. Patients present with fever, anemia, and hepatosplenomegaly, potentially progressing to hemorrhaging, secondary infections, and death. Its pathogenesis is linked to an exaggerated cytokine response. We studied 72 hospitalized patients, analyzing clinical data and outcomes in relation to DNA loads in blood and bone marrow, and plasma concentrations of IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α, and TGF-β. Cytokine levels were found to be elevated. kDNA loads in blood and bone marrow were strongly correlated and increased with disease duration. Higher parasite loads were observed in men, adults, and HIV-infected patients, and they were significantly associated with mortality. IL-6 was independently linked to sepsis. In multivariate analysis, IL-12 was the only cytokine inversely associated with blood parasite load. Parasite load, but not cytokine levels, correlated with disease severity, suggesting additional mechanisms drive progression. IL-12 appears to limit parasitemia, indicating a weak, persistent adaptive immune response that is ultimately overwhelmed by a progressive, inefficient, and inflammatory innate response.